The Role of Intramuscular Lipids in Muscle Anabolic Resistance

 描述（由申请方提供）：肥胖和高脂饮食（HFD）增加了骨骼肌功能障碍的风险，包括合成代谢抵抗，这是一种无法响应进食或生长线索而增加蛋白质合成的疾病。合成代谢抵抗导致肌肉生长在负荷增加的条件下衰减，例如从废用和功能超负荷中恢复。本申请的目的是检查HFD和/或肥胖减少雄性和雌性小鼠中负荷诱导的肌肉生长的机制。我们最近的研究结果表明，在喂食HFD的小鼠中，响应于增加的负荷的肌肉生长显著减弱。这些结果导致了我们的中心假设的形成：饮食诱导的肥胖症中合成代谢抵抗的发展与肌内脂质的积累和脂肪酸中间体的增加有关，导致氧化和内质网（ER）应激的增加，这抑制了响应于增加的负荷的合成代谢信号。为了解决我们的假设，我们提出了三个具体的目标，利用三种小鼠品系（C57 BL/6 J，MuRF 1-/-和ob/ob）和两种负荷诱导的生长模型的独特差异：功能过载和后肢卸载/重装。将使用最先进的成像技术（7-T MRI、激光捕获拉曼光谱和相干反斯托克斯拉曼光谱）测量肌内脂质含量和脂滴大小、数量和组成。在目标1中，我们将检验这样一个假设，即增加高饱和脂肪饮食的持续时间，而不是肥胖，会导致雄性和雌性小鼠合成代谢抵抗的发展。在目标2中，我们将检验HFD导致肌细胞内脂质增加和脂肪酸中间体积累导致合成代谢抵抗发展的假设。在目标3中，我们将检验这样的假设，即HFD的MuRF 1-/-小鼠肌内脂质储存减少，脂肪酸中间体减少，这阻止了合成代谢抗性的发展。这一应用意义重大，因为它将导致我们对肥胖和高饱和脂肪饮食对肌肉响应生长信号能力的影响的理解取得重大进展，这在临床上很重要，因为合成代谢抵抗导致移动性和独立性下降，增加受伤和福尔斯的可能性，并进一步增加糖尿病和心血管疾病的风险。

 DESCRIPTION (provided by applicant): Obesity and high-fat diets (HFD) increase the risk for disorders of skeletal muscle function including anabolic resistance, which is an inability to increase protein synthesis in response to feeding or growth cues. Anabolic resistance leads to the attenuation of muscle growth under conditions of increased loading, such as recovery from disuse and functional overload. The objective of this application is to examine the mechanisms by which a HFD and/or obesity reduces load-induced muscle growth in both male and female mice. Our recent findings reveal that in mice fed a HFD muscle growth in response to increased loading is significantly attenuated. These results have led to the formulation of our central hypothesis: the development of anabolic resistance in diet-induced obesity is related to an accumulation of intramuscular lipids and increased fatty acid intermediates leading to an increase in oxidative and endoplasmic reticulum (ER) stress, which inhibits anabolic signaling in response to increased loading. To address our hypothesis, we propose three specific aims that take advantage of unique differences in three mouse strains (C57BL/6J, MuRF1-/-, and ob/ob) and two load-induced growth models: functional overload and hind limb unloading/reloading. State of the art imaging techniques (7-T MRI, laser trapping Raman spectroscopy, and coherent anti-Stokes Raman spectroscopy) will be used to measure intramuscular lipid content and lipid droplet size, number, and composition. In Aim 1 we will test the hypothesis that increasing duration on a diet high in saturated fats, and not adiposity, leads to the development of anabolic resistance in male and female mice. In Aim 2 we will test the hypothesis that a HFD leads to an increase in intramyocellular lipids and the accumulation of fatty acid intermediates causing the development of anabolic resistance. In Aim 3 we will test the hypothesis that MuRF1-/- mice on a HFD have reduced storage of intramuscular lipids and a decrease in fatty acid intermediates, which prevents the development of anabolic resistance. This application is significant because it will lead to major advances in our understanding of the effects of obesity and diets high in saturated fats on the ability of muscle to respond to growth cues, which is clinically important because anabolic resistance leads to decreased mobility and independence, increases the likelihood of injuries and falls, and further increases the risk for diabetes mellitus and cardiovascular disease.